Research Interests

My main research interests focus on the role of oxidative stress, endothelial dysfunction and hydrogen sulphide (H2S) in the pathologies of pregnancy. Preeclampsia is a complex multifactorial disease, often complicated by fetal growth restriction. Therapeutic interventions so far remain only experimental and there is no established remedy for the treatment of preeclampsia. Placental oxidative stress, a result of deficient spiral artery remodeling, plays an important role in the pathophysiology of preeclampsia and intrauterine growth restriction. I am interested in studying signalling pathways activated by hypoxia-reoxygenation (HR) in the placenta in vivo during labour and in vitro in placental explants. Our results show the beneficial effect of antioxidant vitamins in reducing placental stress in vitro. Antiangiogenic factors secreted from malperfused placenta are instrumental in mediating maternal endothelial dysfunction and consequent symptoms of preeclampsia. I have shown that the antiangiogenic factor sFLT1 alone does not induce activation of endothelial cells, but that it acts in synergy with TNF-α to enhance the pro-inflammatory effects, by antagonising autocrine VEGF-A signalling. These findings uncover a potential mechanism of endothelial dysfunction in pre-eclampsia.

Fetal growth restriction, a leading cause of perinatal morbidity and mortality, is often associated with compromised umbilical arterial flow indicative of increased placental vascular resistance. Hydrogen sulfide, synthesised by cystathionine-γ-lyase, maintains the differentiated smooth muscle phenotype in other vascular beds, and is downregulated in growth-restricted pregnancies. I have acquired strong published and pilot evidence confirming the role of H2S in the pathology of pregnancy, linking reduced H2S production with adverse fetal outcomes. I reported the first evidence of the expression of the H2S-producing enzyme, CSE, in the smooth muscle cells of the placental stem villus arteries (SVAs) and demonstrated KATP dependent-reduction of placental vascular resistance upon exogenous administration of the H2S donor. Crucially, in placentas from intrauterine growth restricted fetuses, as well as pre-eclamptic cases that are accompanied by abnormal UA Doppler profiles, CSE expression is reduced, and this can be recapitulated by subjecting placental explants to HR. There are several projects related to the vascular resistance of SVAs and the role of CSE that I plan to address in the future, including the mechanism of fetal vasoconstriction. I aim to prove the causal link between reduced CSE expression and abnormal umbilical artery Doppler in animal models.

I have also been involved in some ground-breaking research relating to the early placental development where the conceptus develops at a low oxygen environment and it is reliant on histiotrophic support. We have recently published an important study, showing that despite the low oxygen development of the early conceptus there are no differences in the placental metabolomic profile across gestational age in terms of ATP/ADP ratio, NAD+, lactate, or glucose levels, indicating that the first trimester placenta is not compromised energetically. In addition, these data suggest that the hypoxia-induced factor, HIF-1α, is unlikely to play an appreciable role in regulating placental transcriptional activity under steady-state conditions during the first trimester in vivo, but that the pathway may be activated by fluctuations in oxygenation. These findings break the dogma about the hypoxic development of the first trimester pregnancy.